Synaptic plasticity is thought to play a key role in learning and memory, the development of the nervous system, and the recovery of sensory, motor, and cognitive functions after injury. Therefore manipulations that enhance synaptic plasticity have the potential for broad application in the treatment of disorders of learning and development, and for facilitating rehabilitation in cases of disease or injury to the nervous system or periphery. Indeed, there are examples in experimental animals where the enhancement of synaptic plasticity improves learning. Yet there are also examples where the enhancement of synaptic plasticity impairs learning. This project will analyze the factors favoring enhanced versus impaired behavioral outcomes when synaptic plasticity is enhanced. A factor that may limit the ability of enhanced synaptic plasticity to support adaptive changes in the nervous system is the recent history of activity in the neural circuit and the extent to which it saturates the relevant synaptic plasticity mechanism(s). This hypothesis will be tested in the context of the vestibular control of movements, and will leverage the well-characterized circuitry and signaling in that system. The experiments will utilize mice deficient in MHC Class I genes, which have enhanced synaptic plasticity and an impaired ability to adaptively recalibrate their vestibular reflexes through cerebellum-dependent motor learning. Neural activity in the cerebellum will be manipulated behaviorally or directly using optogenetics to manipulate the extent to which plasticity is saturated. A biochemical marker of synaptic plasticity will be used t assess the effect of the recent history of activity on the level of plasticity, and on the capacityfor subsequent vestibular adaptation, in both normal mice and in mice with enhanced synaptic plasticity in the cerebellum. It has been known for many years that the enhancement of synaptic plasticity can, in some cases, enhance learning, but in other cases impair learning, yet there has only been speculation about why this might be the case. This project will provide a rigorous experimental analysis of factors that determine the learning outcome under conditions of enhanced plasticity. In doing so, it will advance our fundamental understanding of how the properties of a synaptic plasticity mechanism, such as its threshold for induction, influence its function in the context of the neural activity in an intact neural circuit. The results can also gude the design of more effective approaches for vestibular rehabilitation, and, more generally, for enhancing plasticity to aid recovery of a wide range of functions after damage to the nervous system.